The ZEB2 gene (zinc finger E-box binding homeobox 2) is located on chromosome 2q22.3. It codes for a member of the ZEB family of zinc finger transcription factors, characterized by two zinc-finger domain clusters for DNA binding and by multiple protein interaction domains. It can participate in both transcriptional activator and, most notably, transcriptional repressor complexes. The ZEB2 gene is expressed in a variety of tissues, with high levels detected in the central nervous system. It plays an essential role in the correct development of the nervous system, from neural crest cell migration in the embryo to pre- and post-natal neurogenesis.
Legend: NIM: NuRD complex interaction motif; NZF, CZF: N- and C-terminal zinc finger cluster; SBD: SMAD binding domain; HD: homeodomain; CID: C-terminal binding protein (CtBP) interacting domain.
The most relevant condition associated with germinal pathogenic variants in the ZEB2 gene is Mowat-Wilson syndrome (MWS; see Clinical section), an autosomal dominant developmental disorder caused by haploinsufficiency (single allele nonsense/frameshift variants and deletions) in nearly all cases. Individuals affected with MWS usually have de novo pathogenic variants; a few cases of parental germinal mosaicism have been described.
ZEB2 has been confirmed to regulate, in a selective way, the differentiation and migration of the GABAergic interneurons to the cerebral cortex, primarily through the downregulation of another transcription factor, Nkx2-1. This mechanism is considered to be the cause of epilepsy in individuals with MWS.
The scientific literature reports a few individuals with missense variants who present with either milder clinical manifestations (e.g. Ghoumid et al. (2013)), or epilepsy/epileptic encelopathy in the absence of the other typical features of MWS (e.g. Nardello et al. (2020)). It is currently being debated whether to include all such cases in the MWS spectrum or to consider them as separate conditions.
Genetic testing
Genetic testing includes direct sequencing of the ZEB2 gene to detect intragenic variants followed by multiplex ligation-dependent probe amplification (MLPA) and/or chromosomal microarray to detect partial or whole locus deletions. Targeted testing may be most appropriate when the clinical suspicion is high, but increasingly patients have been diagnosed following whole exome (WES) or whole genome sequencing (WGS). Panels for intellectual disability and/or epilepsy that include the ZEB2 gene are also appropriate.